血小板與腫瘤細(xì)胞相互作用形成癌栓是腫瘤細(xì)胞發(fā)生轉(zhuǎn)移和遠(yuǎn)端定位的關(guān)鍵血小板可以在以下方面利于腫瘤的血行轉(zhuǎn)移：1）與腫瘤細(xì)胞形成癌栓保護(hù)層而與免疫防御系統(tǒng)隔離,，有利于腫瘤細(xì)胞在循環(huán)運(yùn)輸過程的存活,；2）使腫瘤細(xì)胞成功地抵御了血流的高剪切力的損傷而存活在血液中，從而保護(hù)腫瘤細(xì)胞免受機(jī)體防御機(jī)制的清除。
在小鼠體內(nèi)血小板數(shù)目的減少能抑制腫瘤的生長,，尤其對抑制腫瘤轉(zhuǎn)移來說非常有效，而NK細(xì)胞的缺失卻會逆轉(zhuǎn)血小板的這種抗轉(zhuǎn)移潛能,。因此,，早期研究人員推測血小板可保護(hù)腫瘤細(xì)胞在血行轉(zhuǎn)移過程中免受NK細(xì)胞的抗腫瘤免疫殺傷作用。
腫瘤細(xì)胞并不是作為個(gè)體在血流中傳播,，腫瘤細(xì)胞會與血小板粘附在一起形成癌栓,。癌栓的形成一方面保護(hù)了腫瘤細(xì)胞免受NK細(xì)胞的殺傷，同時(shí)也避免腫瘤細(xì)胞免受血流切力的破壞,。然而,，其中的基本機(jī)制仍不清楚。
近日發(fā)表在Journal of Immunology雜志上的一則研究中,，研究人員證實(shí)巨核細(xì)胞分化過程中可獲得表達(dá)TNF家族成員糖皮質(zhì)激素誘導(dǎo)的腫瘤壞死因子相關(guān)配體（GITRL）,，最終造成血小板表達(dá)GITR。血小板活化后，血小板表面α-顆?；罨瘶?biāo)志物P-選擇素上調(diào)GITRL,。
GITRL也迅速動員血小板表面的粘附分子與腫瘤細(xì)胞相互作用，導(dǎo)致血小板包被住腫瘤細(xì)胞,。而其他幾個(gè)TNF家族成員,，有能力反向轉(zhuǎn)導(dǎo)信號，讓血小板接受GITRL觸發(fā)時(shí)其活化和功能不會發(fā)生變化,。然而,，腫瘤細(xì)胞與血小板之間的癌栓抑制NK細(xì)胞毒性，減少γ-干擾素生產(chǎn)的這兩個(gè)作用可通過阻斷NK細(xì)胞上GITR的活性被部分恢復(fù),，從而表明血小板衍生GITRL通過GITR介導(dǎo)NK細(xì)胞抑制前饋信號,。研究數(shù)據(jù)為進(jìn)一步闡明了血小板是如何參與NK細(xì)胞免疫監(jiān)視腫瘤細(xì)胞的過程。
（生物谷：Bioon.com）
doi:10.4049/jimmunol.1103194
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PMID:
GITR Ligand Provided by Thrombopoietic Cells Inhibits NK Cell Antitumor Activity
Theresa Placke, Helmut R. Salih and Hans-Georg Kopp
Thrombocytopenia inhibits tumor growth and especially metastasis in mice, whereas additional depletion of NK cells reverts this antimetastatic phenotype. It has therefore been speculated that platelets may protect hematogenously disseminating tumor cells from NK-dependent antitumor immunity. Tumor cells do not travel through the blood alone, but are rapidly coated by platelets, and this phenomenon has been proposed to shield disseminating tumor cells from NK-mediated lysis. However, the underlying mechanisms remain largely unclear. In this study, we show that megakaryocytes acquire expression of the TNF family member glucocorticoid-induced TNF-related ligand (GITRL) during differentiation, resulting in GITRL expression by platelets. Upon platelet activation, GITRL is upregulated on the platelet surface in parallel with the α-granular activation marker P-selectin. GITRL is also rapidly mobilized to the platelet surface following interaction with tumor cells, which results in platelet coating. Whereas GITRL, in the fashion of several other TNF family members, is capable of transducing reverse signals, no influence on platelet activation and function was observed upon GITRL triggering. However, platelet coating of tumor cells inhibited NK cell cytotoxicity and IFN-γ production that could partially be restored by blocking GITR on NK cells, thus indicating that platelet-derived GITRL mediates NK-inhibitory forward signaling via GITR. These data identify conferment of GITRL pseudoexpression to tumor cells by platelets as a mechanism by which platelets may alter tumor cell immunogenicity. Our data thus provide further evidence for the involvement of platelets in facilitating evasion of tumor cells from NK cell immune surveillance.
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